Process for forming Form 2 ranitidine hydrochloride

ABSTRACT

A novel crystal form of ranitidine (N-[2-[[[5-(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl-N&#39;-methyl-2-nitro-1,1-ethenediamine) hydrochloride, designated Form 2, and having favorable filtration and drying characteristics, is characterized by its infra-red spectrum and/or by its x-ray powder diffraction patterns.

This application is a dimension of application Ser. No. 406,710, filedAug. 9, 1982, now U.S. Pat. No. 4,521,431, which is a continuation ofSer. No. 307,575, filed Oct. 1, 1981, now abandoned.

The present invention is concerned with the hydrochloride salt of the H₂-antagonist N-[2-[[[5-(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl-N¹ -methyl-2-nitro-1,1-ethenediamine, which has the approved name `ranitidine`, and itsproduction and isolation.

Ranitidine, as described and claimed in British Patent Specification No.1,565,966, shows potent histamine H₂ -blocking activity and may be usedin the treatment of conditions where there is an advantage in loweringgastric acidity, particularly in gastric and peptic ulceration, as aprophylactic measure in surgical procedures, and in the treatment ofallergic and inflammatory conditions where histamine is a knownmediator.

The hydrochloride salt of ranitidine (herinafter referred to asranitidine hydrochloride) is of particular importance since it enablesranitidine to be conveniently formulated in, for example, tablets fororal administration. There thus is the need to produce ranitidinehydrochloride in as pure and as highly crystalline a condition aspossible in order to fulfill exacting pharmaceutical requirements andspecifications.

The process by which the ranitidine hydrochloride is produced also needsto be one which is convenient to operate on a plant scale. In particularit is desirable that the hydrochloride should be prepared withconcentrated hydrochloric acid and that the solvent for crystallisationshould be readily recoverable.

In addition, the product should be in a form that is readily filteredoff and easily dried. It is also desirable that, if required, theproduct can be recrystallised from the same solvent system.

Ranitidine hydrochloride has been obtained in a crystalline form,designated Form 1, by dissolving ranitidine in industrial methylatedspirit containing hydrogen chloride and adding ethyl acetate to thesolution, as described in the above mentioned British PatentSpecification. This procedure, however, does not have the desirablefeatures of a manufacturing process described above and Form 1 of thehydrochloride salt has unsuitable filtration and drying characteristics.

It has now been discovered that ranitidine hydrochloride can be preparedin a new crystalline form having more advantageous properties and themanufacturing process for the said new crystalline form fulfills thedesirable features described above. The present invention thus providesranitidine hydrochloride in a new crystalline form designated Form 2.Form 2 has been found generally to have larger crystals than thehitherto known Form 1 and exhibits more favourable filtration and dryingcharacteristics. Furthermore, Form 2 is less hygroscopic than Form 1,which is an additional advantage in view of the sensitivity ofranitidine hydrochloride to moisture.

Form 2 ranitidine hydrochloride may be characterised by its infra-redspectrum in mineral oil and/or by its X-ray powder diffraction pattern.These will now be discussed in more detail.

INFRA-RED SPECTRUM

The infra-red spectrum of Form 2 ranitidine hydrochloride as a mull inmineral oil shows the following main peaks:

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The infra-red spectrum of the product of Example 1 below obtained inthis way is shown in the accompanying drawings in which the ordinate isthe transmittance in % and the abscissa is the wavenumber in cm⁻¹.

X-RAY DIFFRACTION

The X-ray diffraction pattern of Form 2 ranitidine hydrochloride may beobtained by loading the material into a 0.3 mm diameter glass capillaryand photographing the pattern by the Debye Scherrer method in a 114.6 mmdiameter camera by exposure for 12 hours to CoK_(a) radiation and for 3hours to CuK_(a) radiation (for `d`<3 Å). The weighted mean values ofX-ray wavelengths used for the calculations were CuK_(a) 1.54171 Å andCoK_(a) 1.79024 Å.

The X-ray powder diffraction pattern of Form 2 ranitidine hydrochloridein terms of `d` spacings and relative intensities (I) is a follows(s=strong, m=medium, w=weak, v=very, d=diffuse):

    ______________________________________    d(Å)    I       d(Å)      I    ______________________________________    10.73       m       3.40          2vw    6.50        3vwd    3.35          2vwd    6.13        m       3.25          wd    5.83        s       3.12          2vw    5.63        3vwd    3.04          2vwd    5.42        s       2.97          3vwd    5.06        2vw     2.93          3vwd    4.92        w       2.88          3vwd    4.59        2vw     2.81          vwd    4.40        s       2.72          vwd    4.28        w       2.66          3vwd    3.91        wd      2.47          2vwd    3.79        s       2.44          vw    3.71        m       2.34          2vwd    3.60        vwd     2.30          3vwd    3.46        m       2.21          2vwd    ______________________________________

Form 2 ranitidine hydrochloride may be formulated for administration inany convenient way and the invention includes within its scopepharmaceutical compositions comprising Form 2 ranitidine hydrochlorideadapted for use in human or veterinary medicine. Such compositions maybe presented for use in a conventional manner with the aid of apharmaceutically acceptable carrier or excipient and may also contain ifrequired other active ingredients, e.g. H₁ -antagonists. Thus thehydrochloride salt according to the invention may be formulated fororal, buccal, topical, parenteral, or rectal administration. Oraladministration is preferred, particularly in the form of tablets andcapsules.

For oral administration, the pharmaceutical composition may take theform of for example, tablets, capsules, powders, solutions, syrups orsuspensions prepared by conventional means with acceptable excipients.For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

Form 2 ranitidine hydrochloride may be formulated for parenteraladministration by bolus injection of continuous infusion. Formulationsfor injection may be presented in unit dosage form in ampoules, or inmulti-dose containers, with an added preservative. The composition maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

Form 2 ranitidine hydrochloride may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For topical application, Form 2 ranitidine hydrochloride may beformulated as ointments, creams, gels, lotions, powders or sprays in aconventional manner.

For internal administration a convenient daily dosage regime of Form 2ranitidine hydrochloride is 1 to 4 doses to the total of some 40 mg to1.2 g per day, dependent upon the condition of the patient.

The present invention also provides a process for the preparation ofForm 2 ranitidine hydrochoride which comprises crystallising ranitidinehydrochloride from a solution thereof in a solvent under conditionswhich yield Form 2 ranitidine hydrochloride.

The precise condition under which Form 2 ranitidine hydrochloride isformed may be empirically determined and it is only possible to give anumber of methods which have been found to be suitable in practice.

Thus, for example, Form 2 ranitidine hydrochloride may be prepared bycrystallisation under controlled conditions. In particular, it can beprepared either from the corresponding free base by reaction withhydrochloric acid or by recrystallisation of previously isolatedranitidine hydrochloride. In general the use of a hydroxylic solvent,e.g. a lower alkanol, is preferred. In order to dissolve the startingmaterial it may be helpful to warm and/or to include some water in thesolvent system. In some cases it is necessary to add further organicsolvent or a specific anti-solvent such as acetone in order to bring theForm 2 crystals out of solution.

When the starting material for the preparation of the desired Form 2ranitidine hydrochloride is the free base, one preferred preparationinvolves treating a solution of ranitidine in propan-2-ol withhydrochloric acid, followed by crystallisation of the required form ofthe hydrochloride salt, preferably at an elevated temperature at up to70° C., e.g. 40° to 60° C., particularly 48°-52° C., by addition offurther quantities of propan-2-ol. Alternatively a solution ofranitidine in 2-methylpropanol-2-ol, butan-2-ol or ethanol can betreated with hydrochloric acid and the desired Form 2 ranitidinehydrochloride crystallised at a temperature up to 70° C., for examplefrom room temperature to 60° C. It is preferable to use concentratedhydrochloric acid (e.g. 35 to 38% w/w) and, in general, molar equivalentproportions of hydrochloric acid and ranitidine should be employed.Under these conditions, salt formation, as well as crystallisation,should preferably be carried out at an elevated temperature, for examplewithin the above mentioned temperature ranges. It has been found that itmay be advantageous to include in the starting solution, a small amountto water, additional to that in the hydrochloric acid e.g. up to 7%,preferably about 3% v/v. For example where ehtanol is the solvent, thiscan be used in the form of industrial methylated spirit which containsabout 2% v/v water.

When the starting material is ranitidine hydrochloride e.g. Form 1 orForm 2, the desired Form 2 salt may be crystallised using similarconditions for crystallisation to those described above. Alternatively,the salt may be dissolved, e.g. by warming, in an organic solvent suchas methanol or ethanol followed by cooling of the resulting solution,e.g. to 10° to 40° C., and stirring until crystallisation of therequired form is complete. In the case of some solvents, e.g. methanol,it may be advantageous to add a miscible anti-solvent such as acetone orethyl acetate to the solution to complete crystallisation.

It has frequently been found desirable to add `seeds` of Form 2ranitidine hydrochloride to the crystallisation solution in order toinduce crystallisation.

Form 2 ranitidine hydrochloride has proved to be readily isolable andcan be filtered off from the crystallisation medium, if desired aftercooling, and washed and dried.

If desired, the Form 2 ranitidine hydrochloride prepared as above mayfurther be recrystallised using similar conditions for crystallisationto those described above.

In order that the invention may be more fully understood the followingExamples are given by way of illustration only. All temperatures are in°C. The concentrated hydrochloric acid is 35% w/w and the industrialmethylated spirit is 74° o.p. and contains 2% v/v water.

EXAMPLE 1 Preparation of Form 2 ranitidine hydrochloride

One equivalent (about 5.3 ml) of concentrated hydrochloric acid wasadded to a solution of ranitidine (20 g) in a mixture of propan-2-ol(130 ml) and water (4 ml) at 45°. The mixture was heated at 50° whilst afurther quantity of propan-2-ol (68 ml ) was added and the resultingsolution was then stirred at 50° to allow the product to crystallise.The slurry was cooled to 10° to 12° and the product was filtered off,washed with propan-2-ol (2×27 ml) and dried at 50° under reducedpressure to give Form 2 ranitidine hydrochloride (21 g) m.p. 139°-141°.

EXAMPLE 2 Recrystallisation of ranitidine hydrochloride

Form 2 ranitidine hydrochloride (25 g) was warmed in a mixture ofpropan-2-ol (66 ml) and water (9 ml) and the resulting solution wasstirred at 50°. A further quantity of propan-2-ol (150 ml) was addedover a period of 5 to 10 minutes and the product was allowed tocrystallise at 50°. The slurry was cooled to 10° to 12° and the productwas filtered off, washed with propan-2-ol (2×30) and dried at 50° underreduced pressure to give Form 2 ranitidine hydrochloride (23.6 g) m.p.139°-141°.

EXAMPLE 3 Recrystallisation of ranitidine hydrochloride

Form 2 ranitidine hydrochloride (50 g) was warmed in a mixture ofpropan-2-ol (132 ml) and water (18 ml) and the resulting solutionstirred at 55°. A further quantity of propan-2-ol (300 ml) was addedover a period of 5 to 10 minutes and the product was allowed tocrystallise at 55°. The slurry was cooled to 10° to 12° and the productwas filtered off, washed with propan-2-ol (2×60 ml) and dried at 50°under reduced pressure to give Form 2 ranitidine hydrochloride (48 g)m.p. 141°-142°.

EXAMPLE 4 Recrystallisation of ranitidine hydrochloride

Form 2 ranitidine hydrochloride (50 g) was dissolved in industrialmethylated spirit (200 ml ) at 70°. The solution was allowed to cool andthe product crystallised out at 40°. The resulting slurry was cooled to0° and the product was filtered off, washed with industrial methylatedspirit (20 ml) and dried at 50° under reduced pressure to give Form 2ranitidine hydrochloride (47.7 g) m.p. 140°-142°.

EXAMPLE 5 Preparation of Form 2 ranitidine hydrochloride

Concentrated hydrochloric acid (1.4 ml) was added to a solution ofranitidine (6 g ) in 2-methylpropan-2-ol. The mixture was stirred at 40°to allow the product to crystallise and the resulting slurry was cooledto 20°. Further concentrated hydrochloric acid (about 0.2 ml) was addedto the mixture and, after stirring for 1 h at 20° the product wasfiltered off, washed with 2-methylpropan-2-ol, and dried at 50° underreduced pressure to give Form 2 ranitidine hydrochloride (5.96 g) m.p.141°-142°.

EXAMPLE 6 Preparation of Form 2 ranitidine hydrochloride

The process of Example 5 was repeated, using butan-2-ol instead of2-methylpropan-2-ol and stirring the mixture at 55°, to give Form 2ranitidine hydrochloride (6.1 g) m.p. 140°-141°.

EXAMPLE 7 Recrystallisation of Form 1 ranitidine hydrochloride to giveForm 2 ranitidine hydrochloride

Form 1 ranitidine hydrochloride (25 g) was warmed in a mixture ofpropan-2-ol (66 ml) and water (9 ml) and the resulting solution wasstirred at 50°. A further quantity of propan-2-ol (150 ml) was addedover a period of 5 to 10 minutes and the product was allowed tocrystallise at 50°. The slurry was cooled to 10° to 12° and the productwas filtered off, washed with propan-2-ol (2×30 ml) and dried at 50°under reduced pressure to give Form 2 ranitidine hydrochloride (22.7 g)m.p. 139°-140°.

EXAMPLE 8 Recrystallisation of Form 1 ranitidine hydrochloride to giveForm 2 ranitidine hydrochloride

Form 1 ranitidine hydrochloride (10 g) was warmed in a mixture ofmethanol (15 ml) and acetone (15 ml). The solution was stirred at 50°whilst a further quantity of acetone (45 ml) was added and the resultingsolution was then stirred at 50° to allow the product to crystallise.The slurry was cooled to 20° and the product was filtered off, washedwith acetone (2 ×10 ml), and dried at 50° under reduced pressure to giveForm 2 rantidine hydrochloride (9.5 g) m.p. 141°-142°.

EXAMPLE 9 Preparation of Form 2 ranitidine hydrochloride

Ranitidine (6 g) was dissolved in industrial methylated spirits (42 ml)at ambient temperature (about 20°). One equivalent (about 1.6 ml) ofconcentrated hydrochloric acid was added to the solution. Thetemperature rose to about 27° and the solution was seeded at thistemperature to induce crystallisation. The product crystalised to give athick slurry at 25°-27°. After 0.5 h the slurry was cooled to 10°-12°for 0.5 h. The product was then filtered off, washed with industrialmethylated spirits (5 ml) and dried at 50° under reduced pressure togive Form 2 ranitidine hydrochloride (5.4 g) m.p. 139°-140°.

EXAMPLES 10-12 Preparation of Form 2 ranitidine hydrochloride

Ranitidine (50 g) was dissolved in propan-2-ol (225 ml) at 45°-55°.Celite (0.6 g) was added and the reaction mixture filtered. Propan-2-ol(100 ml) heated to 45°-55° was used to wash the filter. Water (seefollowing Table--omitted in Example 12) was added to the combinedfiltrate and the reaction solution adjusted to the crystallisationtemperature (see table).

Concentrated hydrochloric acid (approximately 14 ml) was added until theend-point was reached i.e. an aliquot of the reaction mixture turnedbromothymol blue from green to yellow. Propan-2-ol (168 ml) warmed to45°-55° was added and the temperature of the solution adjusted to thecrystallisation temperature chosen. The solution was seeded with Form 2ranitidine hydrochloride, if necessary, and left to stir for 3 hours.

The reaction mixture was then cooled to room temperature and stirredovernight. Prior to filtration the mixture was cooled to 8°-12° for 11/2hours. The mixture was filtered and the product washed with cold(8°-12°) propan-2-ol (2×62 ml.). The Form 2 ranitidine hydrochlorideproduct was dried in a vacuum oven at 50°.

                  TABLE    ______________________________________    Example           Vol. of         Crystallisation                                       Yield    No.    Water added (ml)                           Temp. (°C.)                                       (g)    ______________________________________    10     2.1             40          52.2    11     2.1             55          51.0    12     --              50          54.0    ______________________________________

I claim:
 1. A process for the preparation of Form 2 ranitidinehydrochloride characterized by an infra-red spectrum as a mull inmineral oil showing the following main peaks:

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which comprises crystallising ranitidine hydrochloride from a solutionthereof in a solvent under conditions which yield Form 2 ranitidinehydrochloride.
 2. A process as claimed in claim 1, wherein the Form 2ranitidine hydrochloride is prepared from ranitidine free base byreaction with hydrochloric acid.
 3. A process as claimed in claim 2carried out in a hydroxylic solvent.
 4. A process for the preparation ofForm 2 ranitidine hydrochloride characterized by an infra-red spectrumas a mull in mineral oil showing the following main peaks:

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which comprises treating a solution of ranitidine in propan-2-ol withhydrochloric acid at a temperature of up to 70° C. and crystallisingForm 2 ranitidine hydrochloride by addition of further propan-2-ol.
 5. Aprocess for the preparation of Form 2 ranitidine hydrochloridecharacterized by an infra-red spectrum as a mull in mineral oil showingthe following main peaks:

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which comprises treating a solution of ranitidine in2-methylpropan-2-ol, butan-2-ol or ethanol with hydrochloric acid at atemperature of up to 70° C., followed by crystallisation of said Form 2ranitidine hydrochloride.
 6. A process as claimed in claim 4, whereinthe starting solution contains up to 7% v/v water.
 7. A process asclaimed in claim 1, wherein Form 2 ranitidine hydrochloride is preparedby recrystallisation of ranitidine hydrochloride.
 8. A process asclaimed in claim 7, wherein recrystallisation takes place from ahydroxylic solvent.
 9. A process as claimed in claim 7, wherein thesolvent is propan-2-ol, methanol or ethanol.
 10. A process as claimed inclaim 8, wherein a miscible anti-solvent is added to the solution tocomplete crystallisation.